Circadian Control of Pancreatic Beta-cell Maturation

项目摘要/摘要 遵循发育规律，胰岛β细胞适应出生后环境的变化 通过功能成熟。它们获得对葡萄糖有反应的胰岛素分泌，并通过 提高葡萄糖分泌阈值，扩大分泌量。虽然促进贝塔的因素 细胞成熟已被描述，潜在的分子机制及其生理触发 目前仍不清楚。需要对β细胞如何获得其成熟表型的新见解来发展努力 在1型和2型糖尿病发病期间抑制这种表型的丢失，并在功能上产生 干细胞中的成熟β细胞可用于移植治疗。 转录因子Dec1是特定激活的生物钟机制的调节器 在出生后的β细胞成熟过程中。DEC1结合编码关键介体的基因的启动子/增强子 成熟的葡萄糖感应和胰岛素分泌，以及β细胞中Dec1的丢失，使小鼠因 生理上不成熟的小岛。阿尔瓦雷斯博士建议研究这些表型的分子基础， 通过1)检测Dec1缺失对单个胰腺的表观基因组、转录组和蛋白质组的影响 β细胞，以及2)确定Dec1调节的功能伙伴和分子机制 β细胞成熟度。 这些创新的实验补充了阿尔瓦雷斯博士先前的技能，同时提供了新的昼夜节律训练 活体动物研究和单细胞技术。世界一流的导师和合作者团队，拥有领先的 在这些方法以及在β细胞、糖尿病和昼夜生理学方面的经验确保了出色的 指导。此外，一系列正式的、有组织的说教和体验式培训活动旨在 建议促进阿尔瓦雷斯博士作为独立研究员的发展。 总之，拟议的研究和职业发展活动将对阿尔瓦雷斯博士开发一种新的 独立研究计划侧重于将昼夜节律生物学与贝塔细胞生理学联系起来。由此产生的结果 研究计划对于识别和利用治疗机会来管理、预防、甚至是 恢复糖尿病患者成熟β细胞功能的丧失。

PROJECT SUMMARY/ABSTRACT Following developmental specification, pancreatic beta cells adapt to changes in the postnatal environment through functional maturation. They gain glucose-responsive insulin secretion, and gradually refine it by increasing the glucose threshold for secretion and expanding secretory capacity. While factors promoting beta cell maturation have been described, the underlying molecular mechanisms and their physiological triggers remain unclear. New insights into how beta cells acquire their mature phenotype are needed to develop efforts to curb loss of this phenotype during the onset of type 1 and type 2 diabetes, and to generate functionally mature beta cells from stem cells that can be used as transplantation therapy. The transcription factor Dec1 is a modulator of the circadian clock mechanism that is specifically activated during postnatal beta cell maturation. Dec1 binds promoter/enhancers of genes encoding key mediators of mature glucose sensing and insulin secretion, and loss of Dec1 in beta cells renders mice diabetic due to physiologically immature islets. Dr. Alvarez proposes to investigate the molecular basis for these phenotypes, by 1) examining the impact of Dec1 loss on the epigenome, transcriptome, and proteome of single pancreatic beta cells, and 2) determining the functional partners and molecular mechanisms by which Dec1 modulates beta cell maturity. These innovative experiments complement Dr. Alvarez' prior skills while conferring new training in circadian live-animal studies and single-cell technologies. A world-class team of mentors and collaborators with leading experience in these methods and in beta cell, diabetes, and circadian physiology ensures exceptional guidance. In addition, a series of formal, structured didactic and experiential training activities aimed at fostering Dr. Alvarez' development as an independent investigator are proposed. In all, the proposed research and career development activities will be critical to Dr. Alvarez developing a new independent research program focused on linking circadian biology to beta cell physiology. Results from this research program will be important to identify and exploit therapeutic opportunities to manage, prevent, or even restore the loss of mature beta cell function in diabetic patients.